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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jul 12, 2024 |
| Title |
Anti-tumor Efficacy of HRS-4642 and Its Potential Combination with Proteasome Inhibition in KRAS G12D-mutant Cancer [CRISPR] |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrats robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibits promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR/Cas9 screening, which unveiled the proteasome as a synergistic target. We further observed that the proteasome inhibitor, carfilzomib, prominently improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, especially when combined with carfilzomib, significantly reshapes the tumor microenvironment towards an immune permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.
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| Overall design |
genome-wide CRISPR screen in mouse lung cancer and pancreatic cancer cells
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| Contributor(s) |
Zhou C, Li C, Luo L, Li X, Jia K, He N, Mao S, Wang W, Shao C, Liu X, Huang K, Yu Y, Cai X, Chen Y, Dai Z, Li W, Yu J, Li J, Shen F, Wang Z, He F, Sun X, Mao R, Shi W, Zhang J, Jiang T, Zhang Z, Li F, Ren S |
| Citation(s) |
38942026 |
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| Submission date |
May 23, 2024 |
| Last update date |
Jul 12, 2024 |
| Contact name |
Chongyang Li |
| E-mail(s) |
yangyang7305@outlook.com
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| Phone |
18996404748
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| Organization name |
Fudan University
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| Street address |
131 Dong 'an Road, Xuhui District
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| City |
Shanghai |
| ZIP/Postal code |
200032 |
| Country |
China |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| GSM8288544 |
FC1242 Cells, Input, no treament |
| GSM8288545 |
FC1242 Cells, DMSO Treatment for 2 weeks |
| GSM8288546 |
FC1242 Cells, HRS-4642 Treatment for 2 weeks |
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| Relations |
| BioProject |
PRJNA1115528 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE268242_FC-Kras.count.txt.gz |
2.0 Mb |
(ftp)(http) |
TXT |
| GSE268242_FC-Kras.count_normalized.txt.gz |
3.1 Mb |
(ftp)(http) |
TXT |
| GSE268242_KP-Kras.count.txt.gz |
2.0 Mb |
(ftp)(http) |
TXT |
| GSE268242_KP-Kras.count_normalized.txt.gz |
3.3 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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